Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof

ABSTRACT

A method and device for treating a mammalian organism to obtain a desired local or systemic physiological or pharmacological effect is provided. The method includes administering a sustained release drug delivery system to a mammalian organism in need of such treatment at an area wherein release of an effective agent is desired and allowing the effective agent to pass through the device in a controlled manner. The device includes an inner core or reservoir including the effective agent, an impermeable tube which encloses portions of the reservoir, and a permeable member at an end of the tube.

This application is related to U.S. patent application Ser. No.08/919,221, by Chen et al., filed Aug. 28, 1997, entitled SustainedRelease Drug Delivery Devices, now U.S. Pat. No. 5,902,598, which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel sustained release drug deliverydevice, and more particularly to a multilayered drug delivery device.

2. Brief Description of the Related Art

Over the years, various drugs have been developed to assist in thetreatment of a wide variety of ailments and diseases. However, in manyinstances such drugs are hot capable of being administered either orallyor intravenously without the risk of various deleterious side effects.

For example, intravenous ganciclovir (GCV) is effective in the treatmentof cytomegalovirus (CMV) retinitis in AIDS patients, but bone marrowtoxicity limits its usefulness. The incidence of neutropenia (absoluteneutrophil count <1000) during intravenous GCV therapy ranges from 30 to50%. Continuous maintenance GCV therapy is necessary to preventprogression or recrudescence of the disease, but despite maintenancetherapy, 30 to 50% of patients experience a relapse during treatment.Other problems associated with systemic GCV administration include therisk of sepsis related to permanent indwelling catheters and theinability to receive concurrent therapy with zidovudine (AZT) which hasbeen shown to prolong life and improve the immune function in AIDSpatients.

Intravitreal GCV injections of 200 to 400 μg administered once or twiceweekly have resulted in temporary remission of CMV retinitis in AIDSpatients. Intravitreal GCV injections may provide a higher intraoculardrug concentration than systemic therapy and reduce the incidence ofneutropenia. Current treatment of CMV retinitis in AIDS patients isclearly suboptimal. Ganciclovir is virustatic and thus diseaseinhibition requires maintenance drug administration.

Due to the risks that certain drugs impose, researchers have developedsystems for administering such drugs to aid in the treatment of theseailments and diseases. Many of these systems provide a release ratewhich reduces the occurrence of detrimental side effects.

With conventional dosing (tablets, injections, etc.), the concentrationof drug in a given area of the body increases through an ineffectiveconcentration to some concentration that is effective. Frequently theconcentration may actually reach some toxic threshold. After arelatively short period, however, the drug concentration decreases asdrug is either metabolized in the body or is eliminated. Frequently,drug levels decrease so low that therapeutic levels are no longermaintained. A second dose is then given and the cycle is repeated. Thegoal of sustained release systems is to maintain drug levels within thetherapeutic range and ideally a constant level.

In order to achieve constant levels, drugs should be released from adelivery system at a rate that does not change with time (so calledzero-order release). In many systems, however, the release rate isproportional to time (i.e., “first order”) or the square root of time(or Fickian).

Linear release is achievable with some types of reservoir systems, suchas tubes, fibers laminates, or microspheres. In these systems, a drugreservoir is coated in a rate controlling membrane. Drug diffusionacross the membrane is rate limiting and is constant (zero order) aslong as the membrane's permeability does not change and as long as theconcentration of drug in the reservoir is constant (i.e. as long asthere is an excess of drug in the reservoir).

In matrix systems, drug is dispersed throughout a matrix and is releasedas it dissolves and diffuses through the matrix. A drug is released fromthe outer surface of the matrix first, this layer becomes depleted, anddrug that is released from further within the core of the device mustthen diffuse through the depleted matrix. The net result is that therelease rate slows down and Fickian release is common. With matrixsystems, zero-order release is very difficult to achieve. The sameprinciples apply to release from gels.

In some bioerodible systems, diffusion through the matrix is designed tobe extremely slow and drugs are intended to be released as the system isdegraded. It has been generally found to be extremely difficult to usethis approach to achieve a zero-order release, as most polymers do notundergo zero-order degradation. “S” type kinetics are more common. Ageneral discussion of drug delivery control systems is provided inControlled Drug Delivery Systems (Part I), Xue Shen Wu, Ph.D. pp. 32,33, 44-46, 63, 66, and 67 (Technomic Publishing Co, Inc., 1996), theentire contents of which are incorporated herein by reference.

One such delivery device is an orally administered pill or capsule whichcontains a drug encapsulated within various layers of a composition thatdissolves over a period of time in the digestive tract, thereby allowinga gradual or slow release of the drug into the system.

Another type of device for controlling the administration of such drugsis produced by coating a drug with a polymeric material permeable to thepassage of the drug to obtain the desired effect. Such devices areparticularly suitable for treating a patient at a specific local areawithout having to expose the patient's entire body to the drug. This isadvantageous because any possible side effects of the drug could beminimized.

Such systems are particularly suitable for treating ailments affectingthe eye. Advances for administering a drug to the external surface ofthe eye are disclosed in U.S. Pat. No. 4,014,335, to Arnold. Arnolddescribes various ocular inserts that act as a deposit or drug reservoirfor slowly releasing a drug into the tear film for prolonged periods oftime. These inserts are fabricated of a flexible polymeric material thatis biologically inert, non-allergenic, and insoluble in tear fluid. Toinitiate the therapeutic programs of these devices, the ocular insertsare placed in the cul-de-sac between the sclera of the eyeball and theeyelid for administering the drug to the eye.

Devices formed of polymeric materials that are insoluble in tear fluidretain their shape and integrity during the course of the needed therapyto serve as a drug reservoir for continuously administering a drug tothe eye and the surrounding tissues at a rate that is not effected bydissolution or erosion of the polymeric material. Upon termination ofthe desired therapeutic program, the device is removed from thecul-de-sac.

Another type of device used for sustained release of a drug to theexternal surface of the eye, described in U.S. Pat. No. 3,416,530, ismanufactured with a plurality of capillary openings that communicatebetween the exterior of the device and the interior chamber, whichgenerally defined from a polymeric membrane. While these capillaryopenings in this construction are effective for releasing certain drugsto the eye, they add considerable complexity to the manufacture of thedevice because it is difficult to control the size of these openings inlarge scale manufacturing using various polymers.

Another device, described in U.S. Pat. No. 3,618,604, does not involvesuch capillary openings, but instead provides for the release of thedrug by diffusion through a polymeric membrane. The device, in apreferred embodiment, as disclosed in that patent, comprises a sealedcontainer having the drug in an interior chamber. Nonetheless, asdescribed in U.S. Pat. No. 4,014,335, certain problems have beenidentified with such devices such as the difficult task of sealing themargins of the membrane to form the container. In addition, stresses andstrains introduced into the membrane walls from deformation duringmanufacturing of those devices may cause the reservoir to rupture andleak.

Another such device, described in U.S. Pat. No. 4,014,335, comprises athree-layered laminate having a pair of separate and discrete first andthird walls formed of a material insoluble in tear fluid with one of thewalls formed of a drug release material permeable to the passage of drugand the other wall formed of a material impermeable to the passage ofthe drug.

The above described systems and devices are intended to providesustained release of drugs effective in treating patients at a desiredlocal or systemic level for obtaining certain physiological orpharmacological effects. However, there are many disadvantagesassociated with their use including the fact that it is often timesdifficult to obtain the desired release rate of the drug. The need for abetter release system is especially significant in the treatment of CMVretinitis.

Prior to the development of the present invention, there was developed anovel sustained release delivery device which ameliorated many of theaforementioned problems associated with drug delivery. The device, whichis disclosed in U.S. Pat. No. 5,378,475 (incorporated herein byreference in its entirety), included a first coating essentiallyimpermeable to the passage of the effective agent and a second coatingpermeable to the passage of the effective agent. In the device, thefirst coating covered at least a portion of the inner core; however, atleast a small portion of the inner core is not coated with the firstcoating layer. The second coating layer essentially completely coversthe first coating layer and the uncoated portion of the inner core. Theportion of the inner core which is not coated with the second coatinglayer allows passage of the agent into the second coating layer thusallowing controlled release.

While the devices described in U.S. Pat. No. 5,378,475 solve many of theaforementioned problems pertaining to drug delivery, the devices and themethod of making the devices are not without problems. In particular,polymers suitable for coating the inner core are frequently relativelysoft and technical difficulties can arise in production of uniformfilms. This is especially true when attempting to coat non-sphericalbodies with edges (such as a cylindrical shape). In such case,relatively thick films must be applied to achieve uninterrupted anduniform coatings, which adds significant bulk to the device. Thus, thedevices tend to be larger than necessary as a result of the thicknessneeded to seal the ends of the inner core.

The aforementioned U.S. Pat. No. 5,902,598 presents solutions to theproblems of manufacturing devices which are sized to be effective drugadministration devices in anatomical locations where device volume playsa limiting role in the design of the device. While effective indelivering drugs in situ, some manufacturing difficulties have limitedscaled up manufacturing of these devices. For example, the impermeableinner coating layer of the devices of the aforementioned application,which immediately surrounds the drug reservoir, is typically formed of amaterial the thickness of which results in a layer which is not capableof supporting its own weight.

While beneficial from the standpoint of reducing the overall size of thedevice, and while still sealing the drug reservoir, goals well-addressedin the aforementioned patent, the relative flaccidity of this innerlayer makes it difficult to load the device's reservoir with a drugsolution, drug slurry, or drug suspension. Because this inner layer isessentially structurally incapable of maintaining its shape withoutsignificant collapse, i.e., does not have the dimensional stability orstructural ability to accept a drug core inserted therein withoutchanging shape, a relatively solid drug or drug-containing mixture mustbe used in order to manufacture the device. Loading a drug slurry ontothis inner layer during manufacture which does not hold its own shaperesults in the combination of the drug slurry and inner layer beingextremely difficult to handle without damaging it, because the innerlayer collapses and the drug-containing mixture flows out.

The problem of device size is extremely important in the design ofdevices for implantation into limited anatomical spaces such as the eye.Larger devices require more complex surgery to both implant and remove.The increased complexity may result in complications, longer healing orrecovery periods, and potential side effects (e.g., increased chance ofastigmatism). Furthermore, the extra polymer required to achieve auniform coating reduces the potential volume of the implant and hencelimits the amount of drug that can be delivered, potentially limitingboth efficacy and duration.

As a result of all of the above, there remains a need in the art forimproving the design and the method of preparing devices which provide asustained release of a drug to a patient to obtain a desired local orsystemic physiological or pharmacological effect especially for ocularuse.

SUMMARY OF THE INVENTION

It is, therefore, a primary objective of the present invention toprovide a device suitable for the controlled and sustained release of acomposition effective in obtaining a desired local or systemicphysiological or pharmacological effect.

Another object of the present invention is to provide a method fortreating a mammalian organism, e.g., human, to obtain a desired local orsystemic physiological or pharmacological effect. The method includespositioning the sustained released drug delivery system at an areawherein release of the agent is desired and allowing the agent to passthrough the device to the desired area of treatment.

Another object of the present invention is to provide an ocular devicesuitable for direct implantation into the vitreous of the eye. Suchdevices of the present invention are surprisingly found to providesustained controlled release of various compositions to treat the eyewithout risk of detrimental local and systemic side effects.

Another object of the present invention is to maximize the amount ofdrug contained in an intraocular device while minimizing its size inorder to prolong the duration of the implant.

Another object of the present invention is to provide an ocular deliverysystem that could be applied to an intra-ocular lens to preventinflammation or posterior capsular opacification.

Another object of the present invention is to provide an ocular deliverysystem that could be inserted directly into the vitreous, under theretina, or onto the sclera, and wherein inserting can be achieved byinjecting the system or surgically implanting the system.

According to a first exemplary embodiment, a sustained release drugdelivery system comprises an inner reservoir comprising an effectiveamount of an agent effective in obtaining a desired local or systemicphysiological or pharmacological effect, an inner tube impermeable tothe passage of said agent, said inner tube having first and second endsand covering at least a portion of said inner reservoir, said inner tubesized and formed of a material so that said inner tube is capable ofsupporting its own weight, an impermeable member positioned at saidinner tube first end, said impermeable member preventing passage of saidagent out of said reservoir through said inner tube first end, and apermeable member positioned at said inner tube second end, saidpermeable member allowing diffusion of said agent out of said reservoirthrough said inner tube second end.

According to a second exemplary embodiment, a method for treating amammalian organism to obtain a desired local or systemic physiologicalor pharmacological effect comprises administering a sustained releasedrug delivery system to a mammalian organism in need of such treatment.

According to a third exemplary embodiment, a method for treating amammalian organism for ocular edema and ocular neovascularizationcomprises administering a sustained release drug delivery system to amammalian organism in need of such treatment, the drug delivery systemreservoir comprising an effective amount of a steroid effective toobtain a desired local or systemic physiological or pharmacologicaleffect.

According to a fourth exemplary embodiment, a method for providingcontrolled and sustained administration of an agent effective inobtaining a desired local or systemic physiological or pharmacologicaleffect comprises surgically implanting a sustained release drug deliverysystem at a desired location.

According to a fifth exemplary embodiment, a method of manufacturing asustained drug delivery system comprises the steps of joining an endmember to a length of tube to form a vessel-shaped member, the endmember selected from the group consisting of an impermeable cap and apermeable plug, positioning a reservoir in the vessel-shaped member, thereservoir containing an effective amount of an effective agent, andforming an outer layer around a portion of the vessel-shaped member, theouter layer formed of a material selected from the group consisting of apermeable material and an impermeable material.

Still other objects, features, and attendant advantages of the presentinvention will become apparent to those skilled in the art from areading of the following detailed description of embodiments constructedin accordance therewith, taken in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention of the present application will now be described in moredetail with reference to preferred embodiments of the apparatus andmethod, given only by way of example, and with reference to theaccompanying drawings, in which:

FIG. 1 is an enlarged cross-sectional illustration of one embodiment ofa sustained release drug delivery device in accordance with the presentinvention;

FIG. 2 is an enlarged cross-sectional illustration of a secondembodiment of a sustained release drug delivery device in accordancewith the present invention;

FIG. 3 is an enlarged cross-sectional illustration of a third embodimentof a sustained release drug delivery device in accordance with thepresent invention;

FIG. 4 is a cross-sectional illustration of the embodiment illustratedin FIG. 2, taken at line 4-4; and

FIG. 5 schematically illustrates an embodiment of a method in accordancewith the present invention of fabricating a drug delivery device.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Referring to the drawing figures, like reference numerals designateidentical or corresponding elements throughout the several figures.

More specifically, the present inventors have discovered a device andmethod of preparation thereof that is suitable for the controlled andsustained release of an agent or drug effective in obtaining a desiredlocal or systemic physiological or pharmacological effect. Inparticular, it has been found that by sealing at least one surface of areservoir of the device with an impermeable member which is capable ofsupporting it's own weight, which has dimensional stability, which hasthe ability to accept a drug core therein without changing shape, and/orretains its own structural integrity so that the surface area fordiffusion does not significantly change, manufacture of the entiredevice is made simpler and the device is better able to deliver a drug.

That is, the use of a tube of material to hold the drug reservoir duringmanufacture allows for significantly easier handling of the tube andreservoir, because the tube fully supports both its own weight and theweight of the reservoir. Thus, the tube used in the present invention isnot a coating, because a coating cannot support its own weight. Also,this rigid structure allows the use of drug slurries drawn into thetube, which allows the fabrication of longer cylindrical devices.Furthermore, because of the relative ease of manufacturing devices inaccordance with the present invention, more than one reservoir,optionally containing more than one drug, can be incorporated into asingle device.

During use of the devices, because the size, shape, or both, of the drugreservoir typically changes as drug diffuses out of the device, the tubewhich holds the drug reservoir is sufficiently strong or rigid tomaintain a diffusion area so that the diffusion rate from the devicedoes not change substantially because of the change in the drugreservoir. By way example and not of limitation, an exemplary method ofascertaining if the tube is sufficiently rigid is to form a device inaccordance with the present invention, and to measure the diffusion rateof the drug from the device over time. If the diffusion rate changesmore than 50% from the diffusion rate expected based on the chemicalpotential gradient across the device at any particular time, the tubehas changed shape and is not sufficiently rigid. Another exemplary testis to visually inspect the device as the drug diffuses over time,looking for signs that the tube has collapsed in part or in full.

The use of permeable and impermeable tubes in accordance with thepresent invention provides flow resistance to reverse flow, i.e., flowback into the device. The tube or tubes assist in preventing largeproteins from solubilizing the drug in the drug reservoir. Also, thetube or tubes assist in preventing oxidation and protein lysis, as wellas preventing other biological agents from entering the reservoir anderoding the drug therein.

Turning now to the drawing figures, FIG. 1 illustrates a longitudinalcross sectional view of a drug delivery device 100 in accordance withthe present invention. Device 100 includes an outer layer 110, an innertube 112, a reservoir, drug core, drug supply, drug depot, drug matrix,and/or drug in suspension 114, and an inner cap 116. Outer layer 110 ispreferably a permeable layer, that is, the outer layer is permeable tothe drug contained within reservoir 114. Cap 116 is positioned at oneend of tube 112. Cap 116 is preferably formed of an impermeablematerial, that is, the cap is not permeable to the drug contained withinreservoir 114. Cap 116 is joined at end 118, 120 of inner tube 112, sothat the cap and the inner tube together close off a space in the tubein which reservoir 114 is positioned, and together the cap and innertube form a cup- or vessel-shaped member. Inner tube 112 and cap 116 canbe formed separately and assembled together, or the inner tube and thecap can be formed as a single, integral, monolithic element.

Outer layer 110 at least partially, and preferably completely, surroundsboth tube 112 and cap 116, as illustrated in FIG. 1. While it issufficient for outer layer 110 to only partially cover tube 112 and cap116, and in particular the opposite ends of device 100, the outer layeris preferably formed to completely envelop both the tube and cap toprovide structural integrity to the device, and to facilitate furthermanufacturing and handling because the device is less prone to break andfall apart. While FIG. 1 illustrates cap 116 having an outer diameterthe same as the outer diameter of inner tube 112, the cap can be sizedsomewhat smaller or larger than the outer diameter of the inner tubewithin the spirit and scope of the present invention.

Reservoir 114 is positioned inside inner tube 112, as described above. Afirst end 122 abuts against cap 116, and is effectively sealed by thecap from diffusing drug therethrough. On the end of reservoir 114opposite cap 116, the reservoir is preferably in direct contact withouter layer 110. As will be readily appreciated by one of ordinary skillin the art, as drug is released from reservoir 114, the reservoir mayshrink or otherwise change shape, and therefore may not fully ordirectly contact outer layer 110 at the end of the reservoir oppositecap 116. As outer layer 110 is permeable to the drug in reservoir 114,the drug is free to diffuse out of the reservoir along a first flow path124 into portions of outer layer 110 immediately adjacent to the openend of the reservoir. From outer layer 110, the drug is free to diffusealong flow paths 126 out of the outer layer and into the tissue or otheranatomical structure in which device 100 is inserted or implanted.Optionally, holes can be formed through inner layer 112 to addadditional flow paths 126 between reservoir 114 and permeable outerlayer 110.

As discussed above, by providing inner tube 112 of a relatively rigidmaterial, it is possible to more easily manufacture device 100. By wayof example only and not of limitation, referring to FIG. 5, according toa first embodiment of a process of forming device 100, a length of tubestock material is taken as the starting material. Into the open end oftube 112, opposite cap 116, a drug reservoir 114 is inserted, injected,or otherwise positioned, depending on how viscous the drug reservoirmaterial is when positioned in the tube. If reservoir 114 is relativelystiff i.e., is very viscous or solid, the reservoir can be inserted intotube 112, as with a plunger, pushrod, or the like. If reservoir 114 isrelatively flaccid or fluid, i.e., is not very viscous, the reservoircan be poured, injected, or drawn into the tube (e.g., by vacuum). Thelength of tube, including the drug core, is then cut into multiplesections, each of which form a tube 112. Cap 116 is joined to one end oftube 112, thus forming a closed, cup- or vessel-like structure.Thereafter, owing to the relative rigidity of inner tube 112, the innertube and cap 116 can be handled with relative ease, because the innertube is sized and formed of a material so that it is capable ofsupporting its own weight, the weight of cap 116, and the weight ofreservoir 114, without collapsing. Thereafter, the tube can be coated.

According to yet another embodiment of a process for manufacturing inaccordance with the present invention, reservoir 114 can be insertedinto a mold, along with cap 116, and inner tube 112 can be molded aroundthe reservoir and cap. Further alternatively, cap 116 can be formedintegrally with inner tube 112.

By way of contrast, prior devices, including those which include merelya coating around a drug-containing reservoir, at this stage in themanufacturing process must be specially handled by, for example, formingand placing the reservoir in a carrier which supports the coating andreservoir during handling. As will be readily appreciated by one ofordinary skill in the art, elimination by the present invention of suchadditional manufacturing steps and components simplifies themanufacturing process, which in turn can lead to improvements inrejection rates and reductions in costs.

FIG. 1 illustrates only the positions of the several components ofdevice 100 relative to one another, and for ease of illustration showsouter layer 110 and inner tube 112 as having approximately the same wallthickness. While the walls of outer layer 110 and inner tube 112 may beof approximately the same thickness, the inner tube's wall thickness canbe significantly thinner or thicker than that of the outer layer withinthe spirit and scope of the present invention. Additionally, device 100is preferably cylindrical in shape, for which a transverse cross-section(not illustrated) will show circular cross-sections of the device. Whileit is preferred to manufacture device 100 as a cylinder with circularcross-sections, it is also within the scope of the present invention toprovide cap 116, reservoir 114, inner tube 112, and/or outer layer 110with other cross-sections, such as ovals, ellipses, rectangles,including squares, triangles, as well as any other regular polygon orirregular shapes. Furthermore, device 100 can optionally further includea second cap (not illustrated) on the end opposite cap 116; such asecond cap could be used to facilitate handling of the device duringfabrication, and would include at least one through hole for allowingdrug from reservoir 114 to flow from the device.

FIG. 2 illustrates a device 200 in accordance with a second exemplaryembodiment of the present invention. Device 200 includes an impermeableinner tube 212, a reservoir 214, and a permeable plug 216. Device 200optionally and preferably includes an impermeable outer layer 210, whichadds mechanical integrity and dimensional stability to the device, andaids in manufacturing and handling the device. As illustrated in FIG. 2,reservoir 214 is positioned in the interior of inner tube 212, in afashion similar to reservoir 114 and inner tube 112, described above.Plug 216 is positioned at one end of inner tube 212, and is joined tothe inner tube at end 218, 220 of the inner tube. While plug 216 mayextend radially beyond inner tube 212, as illustrated in FIG. 2, theplug may alternatively have substantially the same radial extent as, ora slightly smaller radial extent than, the inner tube, within the spiritand scope of the present invention. As plug 216 is permeable to theagent contained in reservoir 214, the agent is free to diffuse throughthe plug from the reservoir. Plug 216 therefore must have a radialextent which is at least as large as the radial extent of reservoir 214,so that the only diffusion pathway 230 out of the reservoir is throughthe plug. On the end of inner tube 212 opposite plug 216, the inner tubeis closed off or sealed only by outer layer 210, as described below.Optionally, an impermeable cap 242, which can take the form of a disc,is positioned at the end of reservoir opposite plug 216. When provided,cap 242 and inner tube 212 can be formed separately and assembledtogether, or the inner tube and the cap can be formed as a single,integral, monolithic element.

Outer tube or layer 210, when provided, at least partially, andpreferably completely surrounds or envelopes inner tube 212, reservoir214, plug 216, and optional cap 242, except for an area immediatelyadjacent to the plug which defines a port 224. Port 224 is, in preferredembodiments, a hole or blind bore which leads to plug 216 from theexterior of the device. As outer layer 210 is formed of a material whichis impermeable to the agent in reservoir 214, the ends of inner tube 212and reservoir 214 opposite plug 216 are effectively sealed of and do notinclude a diffusion pathway for the agent to flow from the reservoir.According to a preferred embodiment, port 224 is formed immediatelyadjacent to plug 216, on an end 238 of the plug opposite end 222 ofreservoir 214. Plug 216 and port 224 therefore include diffusionpathways 230, 232, through the plug and out of device 200, respectively.

While port 224 in the embodiment illustrated in FIG. 2 has a radialextent which is approximately the same as inner tube 212, the port canbe sized to be larger or smaller, as will be readily apparent to one ofordinary skill in the art. For example, instead of forming port 224radially between portions 228, 230 of outer layer 210, these portions228, 230 can be removed up to line 226, to increase the area of port224. Port 224 can be further enlarged, as by forming outer layer 210 toextend to cover, and therefore seal, only a portion or none of theradial exterior surface 240 of plug 216, thereby increasing the totalsurface area of port 224 to include a portion or all of the outersurface area of the plug.

In accordance with yet another embodiment of the present invention, port224 of device 200 can be formed immediately adjacent to radial externalsurface 240 of plug 216, in addition to or instead of being formedimmediately adjacent to end 238 of the plug. As illustrated in FIG. 4,port 224 can include portions 234, 236, which extend radially away fromplug 216. These portions can include large, continuous, circumferentialand/or longitudinal portions 236 of plug 216 which are not enveloped byouter layer 210, illustrated in the bottom half of FIG. 4, and/or caninclude numerous smaller, circumferentially spaced apart portions 234,which are illustrated in the top half of FIG. 4. Advantageously,providing port 224 immediately adjacent to radial external surface 240of plug 216, as numerous, smaller openings 234 to the plug, allowsnumerous alternative pathways for the agent to diffuse out of device 200in the event of a blockage of portions of the port. Larger openings 236,however, benefit from a relative ease in manufacturing, because only asingle area of plug 216 need be exposed to form port 224.

According to yet another embodiment of the present invention, plug 216is formed of an impermeable material and outer layer 210 is formed of apermeable material. A hole or holes are formed, e.g., by drilling,through one or more of inner layer 212, cap 242, and plug 216, whichpermit drug to be released from reservoir 214 through outer layer 210.According to another embodiment, plug 216 is eliminated as a separatemember, and permeable outer layer 210 completely envelopes inner tube212 and cap 242 (if provided). Thus, the diffusion path ways 230, 232are through outer layer 210, and no separate port, such as port 224, isnecessary. By completely enveloping the other structures with outerlayer or tube 210, the system 200 is provided with further dimensionalstability. Further optionally, plug 216 can be retained, and outer layer210 can envelop the plug as well.

According to yet another embodiment of the present invention, inner tube212 is formed of a permeable material, outer layer 210 is formed of animpermeable material, and cap 242 is formed of either a permeable or animpermeable material. Optionally, cap 242 can be eliminated. Asdescribed above, as outer layer 210 is impermeable to the agent inreservoir 214, plug 216, port 224, and optional ports 234, 236, are theonly pathways for passage of the agent out of device 200.

In a manner similar to that described above with reference to FIG. 1,the use of a relatively rigid inner tube 212 allows device 200 to bemore easily manufactured. According to one embodiment of a process forforming device 200, the combination of plug 216 and inner tube 212 isloaded with reservoir 214, similar to how reservoir 114 is loaded intoinner tube 112 and cap 116, described above. Thereafter, if provided,outer layer 210 is formed around plug 216, inner tube 212, reservoir214, and cap 242 when provided, to form an impermeable outer layer, forreasons discussed above. To form port 224, material is then removed fromouter layer 210 to expose a portion of or all of the outer surface ofplug 216, as described above. Alternatively, port 224 can be formedsimultaneously with the formation of outer layer 210, as by masking thedesired area of plug 216.

According to yet another embodiment of a process for manufacturing inaccordance with the present invention, reservoir 214 can be insertedinto a mold, along with plug 216 and cap 242, and inner tube 112 can bemolded around the reservoir, plug, and cap.

The shape of device 200 can be, in a manner similar to that describedabove with respect to device 100, any of a large number of shapes andgeometries. Furthermore, both device 100 and device 200 can include morethan one reservoir 114, 214, included in more than one inner tube 112,212, respectively, which multiple reservoirs can include diverse or thesame agent or drug for diffusion out of the device. In device 200,multiple reservoirs 214 can be positioned to abut against only a singleplug 216, or each reservoir 214 can have a dedicated plug for thatreservoir. Such multiple reservoirs can be enveloped in a single outerlayer 110, 210, as will be readily appreciated by one of ordinary skillin the art.

Turning now to FIG. 3, FIG. 3 illustrates a device 300 in accordancewith a third exemplary embodiment of the present invention. Device 300includes a permeable outer layer 310, an impermeable inner tube 312, areservoir 314, an impermeable cap 316, and a permeable plug 318. A port320 communicates plug 318 with the exterior of the device, as describedabove with respect to port 224 and plug 216. Inner tube 312 and cap 316can be formed separately and assembled together, or the inner tube andthe cap can be formed as a single, integral, monolithic element. Theprovision of permeable outer layer 310 allows the therapeutical agent inreservoir or drug core 314 to flow through the outer layer in additionto port 320, and thus assists in raising the overall delivery rate. Ofcourse, as will be readily appreciated by one of ordinary skill in theart, the permeability of plug 318 is the primary regulator of the drugdelivery rate, and is accordingly selected. Additionally, the materialout of which outer layer 310 is formed can be specifically chosen forits ability to adhere to the underlying structures, cap 316, tube 312,and plug 318, and to hold the entire structure together. Optionally, ahole or holes 322 can be provided through inner tube 312 to increase theflow rate of drug from reservoir 314.

The invention further relates to a method for treating a mammalianorganism to obtain a desired local or systemic physiological orpharmacological effect. The method includes administering the sustainedrelease drug delivery system to the mammalian organism and allowing theagent effective in obtaining the desired local or systemic effect topass through outer layer 110 of device 100, plug 216 of device 200, orplug 318 and outer layer 310 of device 300 to contact the mammalianorganism. The term administering, as used herein, means positioning,inserting, injecting, implanting, or any other means for exposing thedevice to a mammalian organism. The route of administration depends on avariety of factors including type of response or treatment, type ofagent, and preferred site of administration.

The devices in certain embodiments have applicability in providing acontrolled and sustained release of agents effective in obtaining adesired local or systemic physiological or pharmacological effectrelating at least to the following areas: treatment of cancerous primarytumors, (e.g., glioblastoma); inhibition of neovascularization,including ocular neovascularization; edema, including ocular edema;inflammation, including ocular inflammation; chronic pain; arthritis;rheumatic conditions; hormonal deficiencies such as diabetes anddwarfism; and modification of the immune response such as in theprevention of transplant rejection and in cancer therapy. A wide varietyof other disease states may also be prevented or treated using the drugdelivery device of the present invention. Such disease states are knownby those of ordinary skill in the art. For those not skilled in the art,reference may be made to Goodman and Gilman, The Pharmacological Basisof Therapeutics, 8th Ed., Pergamon Press, NY, 1990; and Remington'sPharmaceutical Sciences 18th Ed., Mack Publishing Co., Easton, Pa.,1990; both of which are incorporated by reference herein.

In addition, the devices are suitable for use in treating mammalianorganisms infected with HIV and AIDS-related opportunistic infectionssuch as cytomegalovirus infections, toxoplasmosis, pneumocystis carinii,and mycobacterium avium intercellular.

The devices are particularly suitable for treating ocular conditionssuch as glaucoma, proliferative vitreoretinopathy, macular edema,including diabetic macular edema, age-related macular degeneration,diabetic retinopathy, uveitis, ocular neovascularization, and ocularinfection. The devices are also particularly suitable for use as anocular device in treating mammalian organisms, both human and forveterinarian use, suffering from ocular histoplasmosis, wherein thedevice is surgically implanted within the vitreous of the eye.

As described above, the inner core or reservoir contains an agenteffective in obtaining a desired local or systemic physiological orpharmacological effect. The following classes of agents could beincorporated into the devices of the present invention: anesthetics andpain killing agents such as lidocaine and related compounds andbenzodiazepam and related compounds; anti-cancer agents such as5-fluorouracil, adriamycin and related compounds; anti-inflammatoryagents such as 6-mannose phosphate; anti-fungal agents such asfluconazole and related compounds; anti-viral agents such as trisodiumphosphomonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI,DDC, and AZT; cell transport/mobility impending agents such ascolchicine, vincristine, cytochalasin B, and related compounds;antiglaucoma drugs such as beta-blockers: timolol, betaxol, atenalol,etc; immunological response modifiers such as muramyl dipeptide andrelated compounds; peptides and proteins such as cyclosporin, insulin,growth hormones, insulin related growth factor, heat shock proteins andrelated compounds; steroidal compounds such as dexamethasone,prednisolone and related compounds; corticosteroids such as fluocinoloneacetonide and related compounds; and carbonic anhydaze inhibitors.

In addition to the above agents, other agents are suitable foradministration to the eye and its surrounding tissues to produce a localor a systemic physiologic or pharmacologic beneficial effect. Examplesof such agents include neuroprotectants such as nimodipine and relatedcompounds; antibiotics such as tetracycline, chlortetracycline,bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline,chloramphenicol, gentamycin, and erythromycin; antibacterials such assulfonamides, sulfacetamide, sulfamethizole and, sulfisoxazole;antivirals, including idoxuridine; and other antibacterial agents suchas nitrofurazone and sodium propionate; antiallergenics such asantazoline, methapyriline, chlorpheniramine, pyrilamine, andprophenpyridamine; anti-inflammatories such as hydrocortisone,hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone,medrysone, methylprednisolone, prednisolone 21-phosphate, prednisoloneacetate, fluoromethalone, betamethasone, and triminolone; decongestantssuch as phenylephrine, naphazoline, and tetrahydrazoline; miotics andanti-cholinesterase such as pilocarpine, eserine salicylate, carbachol,di-isopropyl fluorophosphate, phospholine iodine, and demecariumbromide; mydriatics such as atropine sulfate, cyclopentolate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; sympathomimetics such as epinephrine; and prodrugssuch as those described in Design of Prodrugs, edited by Hans Bundgaard,Elsevier Scientific Publishing Co., Amsterdam, 1985. Once again,reference may be made to any standard pharmaceutical textbook such asRemington's Pharmaceutical Sciences for the identify of other agents.

Any pharmaceutically acceptable form of such a compound may be employedin the practice of the present invention, i.e., the free base or apharmaceutically acceptable salt or ester thereof. Pharmaceuticallyacceptable salts, for instance, include sulfate, lactate, acetate,stearate, hydrochloride, tartrate, maleate, and the like.

A large number of materials can be used to construct the devices of thepresent invention. The only requirements are that they are inert,non-immunogenic, and of the desired permeability, as described above.

Materials that may be suitable for fabricating devices 100, 200, and 300include naturally occurring or synthetic materials that are biologicallycompatible with body fluids and/or eye tissues, and essentiallyinsoluble in body fluids with which the material will come in contact.The use of rapidly dissolving materials or materials highly soluble ineye fluids are to be avoided since dissolution of the outer layers 110,210, 310 would affect the constancy of the drug release, as well as thecapability of the system to remain in place for a prolonged period oftime.

Naturally occurring or synthetic materials that are biologicallycompatible with body fluids and eye tissues and essentially insoluble inbody fluids which the material will come in contact include, but are notlimited to: ethyl vinyl acetate, polyvinyl acetate, cross-linkedpolyvinyl alcohol, cross-linked polyvinyl butyrate, ethyleneethylacrylate copolymer, polyethyl hexylacrylate, polyvinyl chloride,polyvinyl acetals, plasiticized ethylene vinylacetate copolymer,polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer,polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides,polymethylmethacrylate, polybutyl-methacrylate, plasticized polyvinylchloride, plasticized nylon, plasticized soft nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polytetrafluorothylene,polyvinylidene chloride, polyacrylonitrile, cross-linkedpolyvinylpyrrolidone, polytrifluorochloroethylene, chlorinatedpolyethylene, poly(1,4′-isopropylidene diphenylene carbonate),vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethylfumerale copolymer, silicone rubbers, especially the medical gradepolydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonatecopolymers, vinylidene chloride-vinyl chloride copolymer, vinylchloride-acrylonitrile copolymer, vinylidene chloride-acrylonitridecopolymer, gold, platinum, and (surgical) stainless steel.

Specifically, outer layer 210 of device 200 may be made of any of theabove-listed polymers or any other polymer which is biologicallycompatible with body fluids and eye tissues, essentially insoluble inbody fluids which the material will come in contact, and essentiallyimpermeable to the passage of the effective agent. The term impermeable,as used herein, means that the layer will not allow passage of theeffective agent at a rate required to obtain the desired local orsystemic physiological or pharmacological effect.

When inner tube 112, 212, 312 is be selected to be impermeable, asdescribed above, to the passage of the agent from the inner core orreservoir out to adjacent portions of the device, the purpose is toblock the passage of the agent to those portions of the device, and thuscontrol the release of the agent out of the drug delivery device throughouter layer 110, plug 216, and plug 318.

The composition of outer layer 110, e.g., the polymer, must be selectedso as to allow the above-described controlled release. The preferredcomposition of outer layer 110 and plug 216 will vary depending on suchfactors as the active agent, the desired rate of control, and the modeof administration. The identity of the active agent is important sincethe size of the molecule, for instance, is critical in determining therate of release of the agent into the outer layer 110 and plug 216.

Caps 116, 242, 316 are essentially impermeable to the passage of theeffective agent and may cover a portion of the inner tube not covered bythe outer layer. The physical properties of the material, preferably apolymer, used for the caps can be selected based on their ability towithstand subsequent processing steps (such as heat curing) withoutsuffering deformation of the device. The material, e.g., polymer, forimpermeable outer layer 210 can be selected based on the ease of coatinginner tube 212. Cap 116 can be formed of one of a number of materials,including PTFE, polycarbonate, polymethyl methacrylate, polyethylenealcohol, high grades of ethylene vinyl acetate (9% vinyl, content), andpolyvinyl alcohol (PVA). Inner tubes 112, 212, 312 can be formed of oneof a number of materials, including PTFE, polycarbonate, polymethylmethacrylate, polyethylene alcohol, high grades of ethylene vinylacetate (9% vinyl, content), and polyvinyl alcohol Plugs 216, 318 can beformed of one of a number of materials, including cross-linked PVA, asdescribed below.

Outer layers 110, 210, 310, and plugs 216, 318 of the device of thepresent invention must be biologically compatible with body fluids andtissues, essentially insoluble in body fluids which the material willcome in contact, and outer layer 110 and plugs 216, 318 must bepermeable to the passage of the agent or composition effective inobtaining the desired effect.

The effective agent diffuses in the direction of lower chemicalpotential, i.e., toward the exterior surface of the device. At theexterior surface of the device, equilibrium is again established. Whenthe conditions on both sides of outer layer 110 or plugs 216, 318 aremaintained constant, a steady state flux of the effective agent will beestablished in accordance with Fick's Law of Diffusion. The rate ofpassage of the drug through the material by diffusion is generallydependent on the solubility of the drug therein, as well as on thethickness of the wall. This means that selection of appropriatematerials for fabricating outer layer 110 and plug 216 will be dependenton the particular drug to be used.

The rate of diffusion of the effective agent through a polymeric layerof the present invention may be determined via diffusion cell studiescarried out under sink conditions. In diffusion cell studies carried outunder sink conditions, the concentration of drug in the receptorcompartment is essentially zero when compared to the high concentrationin the donor compartment. Under these conditions, the rate of drugrelease is given by:

Q/t=(D·K·A·DC)/h

where Q is the amount of drug released, t is time, D is the diffusioncoefficient, K is the partition coefficient, A is the surface area, DCis the difference in concentration of the drug across the membrane, andh is the thickness of the membrane.

In the case where the agent diffuses through the layer via water filledpores, there is no partitioning phenomena. Thus, K can be eliminatedfrom the equation. Under sink conditions, if release from the donor sideis very slow, the value DC is essentially constant and equal to theconcentration of the donor compartment. Release rate therefore becomesdependent on the surface area (A), thickness (h), and diffusivity (D) ofthe membrane. In the construction of the devices of the presentinvention, the size (and therefore, surface area) is mainly dependent onthe size of the effective agent.

Thus, permeability values may be obtained from the slopes of a Q versustime plot. The permeability P, can be related to the diffusioncoefficient D, by:

P=(K·D)/h

Once the permeability is established for the material permeable to thepassage of the agent, the surface area of the agent that must be coatedwith the material impermeable to the passage of the agent may bedetermined. This is done by progressively reducing the available surfacearea until the desired release rate is obtained.

Exemplary microporous materials suitable for use as outer layer 110 andplugs 216, 318, for instance, are described in U.S. Pat. No. 4,014,335,which is incorporated herein by reference in its entirety. Thesematerials include cross-linked polyvinyl alcohol, polyolefins orpolyvinyl chmorides or cross-linked gelatins; regenerated, insoluble,non-erodible cellulose, acylated cellulose, esterified celluloses,cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, cellulose acetate diethyl-aminoacetate;polyurethanes, polycarbonates, and microporous polymers formed byco-precipitation of a polycation and a polyanion modified insolublecollagen. Cross-linked polyvinyl alcohol is preferred for both outerlayer 110 and plugs 216, 318.

The devices of the present invention may be made in a wide variety ofways, portions of which are described in greater detail above. Once thereservoir and inner tube have been assembled along with caps 116, 242 orplugs 216, 318, the outer layer may be applied. The outer layer may beapplied by dipping the device one or more times in a solution containingthe desired polymer. Optionally, the outer layer may be applied bydropping, spraying, brushing or other means of coating the outer surfaceof the device with the polymer solution. When using a polyvinyl alcoholsolution to obtain the outer layer, the desired thickness may beobtained by applying several coats. Each coat may be dried prior toapplying the next coat. Finally, the device may be heated to adjust thepermeability of outer layer 110 or plugs 216, 318.

Impermeable polymer layers in devices in accordance with the presentinvention should be thick enough to prevent release of drug across themexcept for the area not covered, e.g., port 224. Due to the desirabilityof minimizing the size of the implantable devices, the thickness of animpermeable layer therefore can be between about 0.01 and about 2millimeters, preferably between about 0.01 and about 0.5 millimeters,most preferably between about 0.01 and about 02 millimeters.

Caps 116, 242 should also be thick enough to prevent drug release acrossit. Due to the desirability of minimizing the size of the implants, thethickness of the impermeable cap 116 can be between about 0.01 and about2 millimeters, preferably between about 0.01 and about 0.5 millimeter,most preferably between about 0.01 and about 0.2 millimeter.

The above description of how to make the devices of the presentinvention is merely illustrative and should not be considered aslimiting the scope of the invention in any way, as various compositionsare well known by those skilled in the art. In particular, the methodsof making the device depends on the identity of the active agent andpolymers selected. Given the active agent, the composition of the outerlayers, the inner tube, the plug, and the cap, one skilled in the artcould easily make the devices of the present invention usingconventional coating techniques.

The method for treating a mammalian organism to obtain a desired localor systemic physiological or pharmacological effect includesadministering the sustained release drug delivery device of the presentinvention to the mammalian organism and allowing the agent to passthrough the device to come in direct contact with the mammalianorganism.

The drug delivery system of the present invention may be administered toa mammalian organism via any route of administration known in the art.Such routes of administration include intraocular, oral, subcutaneous,intramuscular, intraperitoneal, intranasal, dermal, into the brain,including intracranial and intradural, into the joints, includingankles, knees, hips, shoulders, elbows, wrists, directly into tumors,and the like. In addition, one or more of the devices may beadministered at one time, or more than one agent may be included in theinner core or reservoir, or more than one reservoir may be provided in asingle device.

The drug delivery system of the present invention is particularlysuitable for direct implantation into the vitreous of the eye and forapplication to an intraocular lens.

These methods of administration and technique for their preparation arewell known by those of ordinary skill in the art. Techniques for theirpreparation are set forth in Remington's Pharmaceutical Sciences.

The drug delivery system may be administered for a sufficient period oftime and under conditions to allow treatment of the disease state ofconcern.

For localized drug delivery, the devices may be surgically implanted ator near the site of action. This is the case for devices of the presentinvention used in treating ocular conditions, primary tumors, rheumaticand arthritic conditions, and chronic pain.

For systemic relief the devices may be implanted subcutaneously,intramuscularly, intraarterially, intrathecally, or intraperitoneally.This is the case when devices are to give sustained systemic levels andavoid premature metabolism. In addition, such devices may beadministered orally.

In one embodiment of the invention, an ocular device containingfluocinolone acetonide as the effective agent in a therapeuticallyeffective amount to reduce or prevent ocular neovascularization may beprepared. Such devices may be used to effectively combat and inhibitundesirable ocular neovascularization, edema, or inflammation whensurgically implanted into the vitreous of the eye. Such devices mayremain in the vitreous permanently after treatment is complete. Thepreferred amount of fluocinolone acetonide used in these devices rangesfrom about 0.01 mg to about 40 mg. More preferably, such devices containfrom about 0.1 mg to about 6 mg of fluocinolone acetonide. Thesepreferred ranges may provide sustained release of the fluocinoloneacetonide for a period of from several hours to over five years.Preferred permeable layers in accordance with the present invention areformed of polyvinyl alcohol, which is preferably cross-linked. Preferredimpermeable portions of devices 100, 200, e.g., cap 116 and inner tubes112, 212, are formed of PTFE or ethyl vinyl alcohol.

When such devices are prepared for implantation within the vitreous ofthe eye, it is preferred that the device does not exceed about 7millimeters in any direction, so that the device can be inserted througha less than 7 millimeter incision. Thus, the cylindrical devicesillustrated in FIGS. 1 and 2 would preferably not exceed 7 millimetersin height or 3 millimeters in diameter. The preferred thickness of thewalls of inner tubes 112, 212 ranges between about 0.01 mm and about 1.0mm. The preferred thickness of the wall of outer layer 110 rangesbetween about 0.01 mm and about 1.0 mm. The preferred thickness of thewall of outer layer 210 ranges between about 0.01 mm and 1.0 mm.

While the above described embodiments of the invention are described interms of preferred ranges of the amount of effective agent, andpreferred thicknesses of the preferred layers, these preferences are byno means meant to limit the invention. As would be readily understood byone skilled in the art, the preferred amounts, materials and dimensionsdepend on the method of administration, the effective agent used, thepolymers used, the desired release rate and the like. Likewise, actualrelease rates and release duration depend on a variety of factors inaddition to the above, such as the disease state being treated, the ageand condition of the patient, the route of administration, as well asother factors which would be readily apparent to those skilled in theart. All of the foregoing U.S. patents and other publications areexpressly incorporated by reference herein in each of their entireties.

From the foregoing description, one of ordinary skill in the art caneasily ascertain the essential characteristics of the instant invention,and without departing from the spirit and scope thereof, can makevarious changes and/or modifications of the invention to adapt it tovarious usages and conditions. As such, these changes and/ormodifications are properly, equitably and intended to be, within thefull range of equivalence of the following claims.

1-40. (canceled)
 41. A method for treating a mammal to obtain a desiredlocal or systemic physiological or pharmacological effect, comprisingadministering to the mammal a sustained release drug delivery system,wherein: (i) the system comprises: a drug reservoir comprising atherapeutically effective amount of an agent; an inner tube covering atleast a portion of the drug reservoir, wherein the inner tube has afirst open end and a second open end, the diameter of the inner tube isnot more than 3 millimeters, and the inner tube is dimensionally stableand capable of supporting its own weight; and an outer layer, covering aportion of the inner tube, wherein the outer layer is permeable to thepassage of the agent; and (ii) upon administering the system, the agentis released through at least one of the first open end and second openend.
 42. The method of claim 41, wherein the inner tube is impermeableto the passage of the agent.
 43. The method of claim 41, wherein theinner tube is permeable to the passage of the agent.
 44. The method ofclaim 41, wherein the inner tube comprises a polymer or a metal.
 45. Themethod of claim 44, wherein the inner tube comprises gold, platinum, orstainless steel.
 46. The method of claim 41, wherein the inner tube orouter layer comprises ethyl vinyl acetate, polyvinyl acetate,cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate,ethylene ethylacrylate copolymer, polyethyl hexylacrylate, polyvinylchloride, polyvinyl acetals, plasticized ethylene vinylacetatecopolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloridecopolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal,polyamides, polymethylmethacrylate, polybutyl methacrylate, plasticizedpolyvinyl chloride, plasticized nylon, plasticized soft nylon,plasticized polyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene,polyvinylidene chloride, polyacrylonitrile, cross-linkedpolyvinylpyrrolidone, polytrifluorochloroethylene, chlorinatedpolyethylene, poly(1,4′-isopropylidene diphenylene carbonate),vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethylfumarate copolymer, silicone rubbers, ethylene-propylene rubber,silicone-carbonate copolymers, vinylidene chloride-vinyl chloridecopolymer, vinyl chloride-acrylonitrile copolymer, or vinylidenechloride-acrylonitrile copolymer.
 47. The method of claim 46, whereinthe outer layer comprises polyvinyl alcohol.
 48. The method of claim 41,wherein the length of the tube is not more than 7 millimeters.
 49. Themethod of claim 41, wherein the agent is a corticosteroid.
 50. Themethod of claim 49, wherein the corticosteroid is fluocinoloneacetonide.
 51. The method of claim 50, wherein administering comprisesinserting the system into the mammal.
 52. The method of claim 51,wherein inserting comprises injecting the system at a desired location.53. The method of claim 52, wherein the location is selected from thevitreous of the eye, under the retina, and onto the sclera.
 54. Themethod of claim 51, comprising inserting the system into the vitreous ofthe eye.
 55. The method of claim 54, wherein inserting comprisesinjecting the system into the vitreous of the eye.
 56. The method ofclaim 41, wherein the mammal is a human.
 57. A method for treating ahuman to obtain a desired local or systemic physiological orpharmacological effect, comprising administering to the human asustained release drug delivery system, wherein: (i) the systemcomprises: a drug reservoir comprising a therapeutically effectiveamount of an agent; an inner tube covering at least a portion of thedrug reservoir, wherein the inner tube has a first open end and a secondopen end, the diameter of the inner tube is not more than 3 millimeters,the length of the inner tube is not more than 7 millimeters, and theinner tube is dimensionally stable and capable of supporting its ownweight; and an outer layer, covering a portion of the inner tube,wherein the outer layer is permeable to the passage of the agent; (ii)administering comprises inserting the system into the vitreous of theeye; and (iii) upon administering the system, the agent is releasedthrough at least one of the first open end and second open end.
 58. Themethod of claim 57, wherein the agent is a corticosteroid.
 59. Themethod of claim 58, wherein the corticosteroid is fluocinoloneacetonide.
 60. The method of claim 57, wherein inserting comprisesinjecting the system into the vitreous of the eye.